We reported a unique combination of sickle cell anemia, hydroxyurea treatment, and short-latency leukemia of erythroid origin that presented a diagnostic challenge and underscored leukemogenic potential. A 33-year-old man with sickle cell anemia began treatment with hydroxyurea, 9.0 mg/kg daily, after 1 year of ambulatory pain and recurrent priapism requiring hospitalization. At baseline, the patient had a leukocyte count of 14 700 109 cells/L, hemoglobin level of 7.2 g/dL, and fetal hemoglobin level of 5.1%. Four years later, he was receiving hydroxyurea, 18 mg/kg daily, and the response was excellent (maximum fetal hemoglobin level, 35.6%; maximum mean corpuscular volume, 131.0 fL), although administration was interrupted by onset of transient neutropenia. The patient was later hospitalized and received transfusions for the acute chest syndrome. Hydroxyurea was withheld due to onset of neutropenia 2 weeks later. Follow-up again showed profound neutropenia (absolute neutrophil count, 0.120 109 cells/L), a leukocyte count of 0.670 109 cells/L, and a platelet count of 102 000 109 cells/L. Peripheral blood smear showed 44% blasts, consistent with normoblasts, megaloblastic changes, and marked dyserythropoiesis in numerous circulating nucleated erythrocytes. We ruled out delayed transfusion reaction and folate or B12 deficiency. Bone marrow biopsy showed hypercellularity with myeloid hypoplasia and erythroid hyperplasia with markedly left-shifted maturation and an increased erythroblast count. There was no increase in myeloblast count. Immunocytochemistry showed that blasts were positive for spectrin, hemoglobin, and CD117 and were negative for myeloperoxidase, CD34, glycophorin, terminal deoxynucleotidyl transferase, CD68, and factor VIII (von Willebrand factor), indicating malignant cells of early erythroid origin. Standard flow cytometry showed less than 2% myeloblasts. Pure erythroid leukemia (Di Guglielmo disease or French-American-British M6b AML) was suspected; however, massive erythroid recovery due to marrow infarctions occurring during the acute chest syndrome was also in the differential diagnosis. Cytogenetic analysis showed that 14 out of 20 marrow metaphase cells were abnormal, with significant karyotypic heterogeneity. The composite karyotype had 44 to 46 chromosomes with a recurring unbalanced rearrangement of chromosome arm 5q, deletion of chromosome arm 7q, loss of chromosomes 15 to 22 and Y, and 5 marker chromosomes, suggesting the myelodysplastic syndrome or AML. Clonal abnormalities enabled diagnosis of pure erythroid leukemia. Induction therapy with cytarabine and idarubicin produced a cytogenetic remission. Sibling-matched stem cell transplantation after cyclophosphamide therapy, fludarabine therapy, and irradiation was unsuccessful, and relapse occurred 4 months later. Flow cytometry demonstrated that 33% blasts were coexpressing CD117, CD38, and CD33. Bone marrow biopsy showed sheets of erythroblasts. Neither salvage chemotherapy nor donor lymphocyte infusion yielded a response. The patient died 9 months after diagnosis. To our knowledge, this is the first case of sickle cell anemia associated with AML of erythroid origin and a complex karyotype that meets the immunophenotype criteria for pure erythroid leukemia and, of note, therapy-related AML following the 2008 World Health Organization classification. This case is unique for development after 50 months of hydroxyurea treatment compared with an average AML latency of 8 years in myeloproliferative disorders. Short latency and genomic instability suggest a therapy-related cause, although complex karyotype AML is not characteristic of hydroxyurea treatment in the absence of a myeloproliferative disorder. The potential role of antimetabolites in therapy-related AML and suggestions for expanding hydroxyurea treatment to children and others with sickle cell anemia not meeting current U.S. Food and Drug Administration guidelines highlight the need for long-term studies with bone marrow cytogenetics to determine whether these rare cases represent true therapy-related AML in patients with sickle cell anemia. Even if risk for therapy-related AML was proven, it would need to be weighed against the intrinsic mortality of untreated sickle cell anemia. In another report, we described a novel finding of a CD38 negative extramedullary multiple myeloma (MM) with a prominent antigenic drift. Given that patients with MM live longer after the introduction of novel therapies, it seems reasonable to believe that this phenomenon will become increasingly common. Clinically, since the disease biology typically is more aggressive when there is extramedullary relapse, it is important for clinicians and diagnostic laboratories to be aware and suspect biological variations in this setting, so that appropriate therapy and clinical management decisions can be initiated without unnecessary delays. In the past, overall survival for patients with multiple myeloma (MM) was estimated at around 35 years. After the introduction of high-dose melphalan chemotherapy followed by autologous stem cell rescue, and novel agents (such as bortezomib and immunomodulatory drugs), the nature of treating MM has dramatically changed by nearly doubling overall survival. With such an improvement in the survival of patients with MM, the question remains whether disease biology and local microenvironment interactions evolve to facilitate more highly aggressive forms of the disease, such as extramedullary relapse. Indeed, the frequency of extramedullary disease seems to be higher in the relapse setting compared to newly diagnosed patients with MM. Although there is lack of scientific evidence, one may speculate that dynamic changes seen in the relapse setting may be supported by current novel therapeutics impacting local marrow microenvironment interactions, allowing neoplastic plasma cells to harbor and survive in a different environment. Such disease biology may not respond to conventional therapeutic strategies. Also, from a diagnostic standpoint, neoplastic cells in patients with relapsed and refractory MM may or may not express conventional markers due to altered biology. These findings suggest there may be gradually increasing diagnosis- and treatment-related challenges in relapsed MM in the future.